CN1310622A - 丙戊酸类似物在治疗和预防偏头痛与情感性疾病中的应用 - Google Patents
丙戊酸类似物在治疗和预防偏头痛与情感性疾病中的应用 Download PDFInfo
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Abstract
本发明涉及通过施用治疗有效量的丙戊酸类似物2-正-丙基-4-己炔酸来治疗和预防偏头疼与情感性疾病的方法。化合物2-正-丙基-4己炔酸是有效的抗偏头痛和抗情感性疾病的药物,与丙戊酸相比,其在诱导神经毒性和致畸潜在可能性方面的副作用大大降低。因此,本发明提供了治疗和预防偏头痛和情感性疾病的改进的方法。
Description
本申请要求1998年6月22日提交的序号为60/09281的美国临时申请的优先权。
发明领域
本发明涉及丙戊酸类似物2-正-丙基-4-己炔酸和其在治疗和预防偏头疼与情感性疾病中的应用。据信,本发明丙戊酸类似物是有效的抗偏头痛和抗情感性疾病的药物,与丙戊酸相比,其在诱导神经毒性和致畸潜在可能性方面的副作用大大降低。因此,本发明提供了治疗和预防偏头痛和情感性疾病的改进的方法。
发明背景
偏头痛定义为以头痛(通常为单侧)、恶心呕吐、畏光、音响恐怖、眩晕和全身乏力为特征的周期性发作的血管性头痛。偏头痛是最常见的血管性头痛,世界人群中发病率高达15%。在偏头痛的各种类型中,以典型偏头痛和普通偏头痛最为普遍。两种偏头痛的主要区别在于:典型偏头痛在发作前有神经性症状为先导,而普通偏头痛没有此类先导症状。偏头痛是由间歇性脑功能障碍引起的。然而,所涉及的确切病理生理机制尚不清楚。据信,头痛与血管扩张和脑部缓解头痛的化学递质减少有关。
镇痛药常被用于治疗不常见的和轻度的偏头痛。镇痛药缓解偏头痛的疼痛,而当镇痛药是阿司匹林时,还能够抑制血小板聚集。但是,对于中度到重度偏头痛,使用更强的药物如麦角胺和丙戊酸是必要的。麦角胺酒石酸盐是抵销头疼时疼痛性血管扩张状态的血管收缩剂。在发作早期服用,麦角胺酒石酸盐有助于减轻典型和普通偏头痛症状。丙戊酸已被证实对于治疗和预防偏头痛均有效,然而,它的抗偏头痛作用机制仍不清楚。据信,丙戊酸增加脑γ-氨基丁酸(GABA)水平,这样可以激活GABA受体并抑制与偏头疼有关的反应。
已有报道称偏头痛、情感性疾病和癫痫之间有某种关系。尽管这三种疾病不同,但它们都是神经系统的发作性调节障碍,其在药理学方面有部分重叠。一些药物如丙戊酸能有效治疗所有三种症状,提示它们存在相同的病理生理机制,而其它药物只能有效治疗一种症状。例如,抗偏头痛有效的β受体阻断剂并不能治疗其它两种症状,而且甚至使抑郁症恶化。
全身-局部(complex-partial)惊厥发作的点燃模型,是基于通过最初重复对边缘结构(如杏仁核basolateral外侧核)的惊厥阈下电刺激诱导进行性惊厥发作并伴有脑电图(EEG)阵发性图像。点燃模型一旦建立,现象将持续数月。既然动物的杏仁核点燃惊厥发作与人全身-局部癫痫发作具有许多共同的神经特征,那么目前点燃模型就是全身-局部癫痫最好的动物模型(Goddard等,1969;Loscher和Schmidt 1988;Loscher 1993)。使用杏仁核点燃模型的一个主要优点是,局部和全身大发作的行为和EEG参数均可测得。而且,据报道,杏仁核点燃模型适于研究诸如偏头痛、情感性疾病和癫痫等随时间加重并且在某种意义上与大量症状性发作有关的疾病。
以前,通过皮下注射戊四唑惊厥实验(PTZ实验)证实,与丙戊酸相比,丙戊酸类似物2-正-丙基-4-己炔酸是一改良的抗癫痫药。从无论使用PTZ实验还是使用杏仁核点燃实验的各种研究的试验结果表明:有效对抗PTZ诱导的惊厥的药物不一定有效对抗杏仁核点燃惊厥,反之亦然(Loscher,W.,和Honack,Dagmar.,欧洲药理学杂志(Eur J.Pharmacol.)(1993),232:147-158;Johnson,D.等,癫痫研究(Epilepsy Res.)(1991),8:64-70)。因而,并非所有抗惊厥药均能有效对抗杏仁核点燃惊厥。换句话说,抗癫痫药物在治疗偏头痛或情感性疾病中未必有效。
近期出版物提示,杏仁核点燃模型适于研究共同具有症状性发作随时间加重的发病机制的癫痫、偏头痛和情感性疾病(R.Post和S.Silberstein,神经病学(Neurology)(1994),44:S37-S47;R.Post and S.Weiss,分子神经生物学(Molecular Neurobiology)(1996),13:33-60)。在杏仁核点燃中,对脑杏仁核的间歇性电刺激最初无效,但是随着重复刺激的进行,生化和生理反应累积增加导致惊厥全面发作。随着惊厥的持续点燃,惊厥开始自发出现。症状程度的进展涉及神经元特性的长-久的变化。试验结果表明,点燃诱导动物出现许多与人情感性疾病、偏头痛和癫痫相同的特征,比如由点燃触发到自发发作、发作期间行为模式变化、和对特定抗癫痫药敏感。因而,杏仁核点燃可以作为研究偏头痛、情感性疾病和癫痫中可能涉及的记忆-样过程的可能发生机制的模型。
美国专利4942182报道,杏仁核点燃诱发的惊厥对药物治疗呈阶段依赖性敏感。在该模型中,卡马西平完全抑制大鼠的杏仁核点燃惊厥,但是不能有效阻止其进展。然而,地西泮能有效抑制早期的惊厥发作,但是在惊厥自发发作的晚期则无效。苯妥英,另一抗癫痫药,作用与地西泮相反,能有效阻断自发性惊厥,但是对点燃早期的惊厥发作无效。
杏仁核点燃模型也是用于评价潜在有用的药物的重要模型,因为它能够提供不同于得自其它惊厥模型的信息。举例来说,卡马西平在包括杏仁核点燃模型在内的数种惊厥模型中是有效的抗惊厥药,但是在戊四唑和大剂量印防己毒素诱导的惊厥中效果较差。
丙戊酸是治疗和预防癫痫、偏头痛和情感性疾病的有效药物。然而,它的作用时间短,而且有严重的副作用如镇静、潜在的致命肝脏毒性和致畸性。已经进行了相当的努力以寻找具有与丙戊酸相同效力但较丙戊酸作用时间长并且极大地减少镇静和致畸作用的丙戊酸类似物(Nau等,美国专利申请08/344810,在此以其全部内容引作参考)。因此,化合物2-正-丙基-4-己炔酸是一改良的抗癫痫药。然而,由于该化合物仅仅在皮下注射戊四唑惊厥实验(PTZ实验)中进行了检验,实验的目的是评价药物抗癫痫的效力,但是,该化合物治疗偏头痛或情感性疾病的效力尚属未知。
发明概述
本发明涉及化合物2-正-丙基-4-己炔酸,含有该化合物的药物组合物,以及它们在治疗和/或预防偏头痛与情感性疾病中的用途。据信,与丙戊酸相比,本发明所用化合物在治疗和预防偏头痛与情感性疾病中有效,并且显示出大为降低的副作用和更长的作用持续时间。
本发明的一个目的是提供治疗和/或预防由各种原因引起的偏头痛与情感性疾病(包括单相性、双相性疾病和急性躁狂症)的方法,方法是通过对需要治疗的个体施用治疗或预防有效量的2-正-丙基-4-己炔酸来实现所述目的的。
本发明另一目的是提供治疗和/预防偏头痛与情感性疾病的药物组合物,与丙戊酸相比,所述药物组合物具有较长的作用持续时间,显示较低的副作用和避免致畸毒性。发明详述
本发明涉及丙戊酸类似物2-正-丙基-4-己炔酸作为治疗和预防偏头痛与情感性疾病药物的应用。
本发明提供通过给个体施用2-正-丙基-4-己炔酸来治疗和预防偏头痛或情感性疾病的方法。2-正-丙基-4-己炔酸的合成和必要的代谢特性在美国专利5786380(实施例7-8和10-11)中被全部公开,在此将其全部内容引入参考。哺乳动物,特别是人,将会从此治疗方法中受益,治疗包括正在出现或有出现风险的任何类型的复发性头痛,尤其是血管性头痛和那些中度或重度头痛。患有偏头痛的个体期望得益于服用2-正-丙基-4-己炔酸。本发明方法包括对个体施用足以减轻或预防偏头痛或情感性疾病的治疗有效量的2-正-丙基-4-己炔酸。
与丙戊酸相比,本发明所用化合物具有大大降低的副作用和致畸性,并且具有较长的作用持续时间。
提供的数据显示,同丙戊酸一样,预期2-正-丙基-4-己炔酸有效对抗杏仁核点燃的惊厥。另外,它仅在其最高试验剂量时出现副作用,而且副作用较丙戊酸轻微得多。因而,2-正-丙基-4-己炔酸提供治疗和预防偏头痛与情感性疾病的改良的方法。
化合物2-正-丙基-4-己炔酸有效治疗双相急性躁狂症。典型的躁狂症状包括语言强迫、运动过多、睡眠需要减少、有打架的想法、夸大其词、判断力差、具有攻击性和可能的敌意。
化合物2-正-丙基-4-己炔酸也有效预防和治疗偏头痛。
对于本领域技术人员而言显而易见的是,本发明所用化合物2-正-丙基-4-己炔酸可以以其对映体形式存在。纯的对映体可以用本领域熟知的方法从消旋体中分离。或者,用手性合成法制备对映体。2-正-丙基-4-己炔酸的单独R和S对映体、消旋体和非消旋混合物均落入本发明保护范围。当使用单个对映体时,如果需要利用S对映体的表观高药代动力学特征的话,优选使用2-正-丙基-4-己炔酸的S对映体。然而,如果需要最大限度地避免致畸副作用的话,则优选R对映体。
按常规方式而言,在治疗此类疾病中所使用的化合物的剂量,将依疾病的严重程度、患者的体重和代谢健康状况而异。对于一般患者群来说,优选的起始剂量将通过常规的剂量-范围研究来决定,此研究如同例如在临床试验阶段所进行的那样。对于个体患者的治疗有效剂量,将通过用滴定法测量施用于个体的达到所需治疗或预防效果同时副作用最小时的给药量来决定。剂量可以与丙戊酸的使用量相同,但是可以基于本文公开的效力和动力学参数进行适当调整或者用常规方法来决定。该化合物的优选起始剂量可以是约1~60mg/kg/天,更优选10-20mg/kg/天。患者服用2-正-丙基-4-己炔酸后的血浆浓度优选为50-100μg/ml。
本发明化合物的施用方法可以是用于治疗给药的任何方法,比如口服、非胃肠道、静脉内、肌内、皮下或直肠给药。
本发明也提供治疗偏头痛的药物组合物。药物组合物除了含有化合物2-正-丙基-4-己炔酸或其盐或其前药之外,还含有添加剂如防腐剂、赋形剂、填充剂、润湿剂、粘合剂、崩解剂、缓冲剂、和/或载体。适宜的添加剂可以例如是碳酸镁、碳酸钙、羧甲基纤维素、淀粉、糖、胶、硬脂酸镁或硬脂酸钙、着色剂或香味剂等等。有大量的各种可药用添加剂可用于药物剂型,适宜添加剂的选择对于药剂领域技术人员来说是常规事件。
组合物可以是片剂、胶囊、粉剂、粒剂、锭剂、栓剂、重组粉剂、或液体制剂如口服或无菌的非肠道溶液或悬浮液。
为了取得给药的一致性,优选本发明组合物以单位剂量形式给药。口服给药的单位剂量形式可以是片剂、胶囊等,单位剂量剂型中可以含有惯常的赋形剂如粘合剂,比如糖浆、阿拉伯胶、明胶、山梨醇、西黄蓍胶或聚乙烯吡咯烷酮;和载体如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或甘油。添加剂可以包括崩解剂如淀粉、聚乙烯吡咯烷酮、淀粉羟乙酸钠或微晶纤维素;防腐剂和可药用润湿剂如十二烷基磺酸钠。
除单位剂量剂型之外,多-剂量剂型也包括在本发明范围之内。缓释组合物,例如,用缓慢释放包衣、微囊包封和/或缓慢溶剂聚合物载体而制备的缓释组合物,对于本领域技术人员而言是显而易见的,因此也囊括在本发明范围之内。
固体口服组合物,可以用混合、填充、压片等常规方法来制备。当使用大量填充剂时,可以重复进行混合操作以使活性物质分散到整个组合物中。这样的操作是本领域惯用手段。片剂可以用普通制药实践中众所周知的方法进行包衣,例如用肠溶衣包衣。
口服液体制剂可以是例如乳液、糖浆或酏剂形式,或者可以是干产品形式,在使用前用水或其它适宜载体重新调配。此类液体制剂可以含有常用的添加剂如悬浮剂,例如山梨醇糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶和氢化的可食用脂肪;乳化剂,卵磷脂、一油酸脱水山梨糖醇酯或阿拉伯胶;非含水载体(可以包括可食用油),例如杏仁油或馏分的椰子油,油酯如甘油脂、聚乙二醇酯或乙醇酯;防腐剂,如甲基或丙基对-羟基苯甲酸酯或山梨酸;以及如果需要,还含有常用的香味剂或着色剂。
对于非肠道给药,可以使用化合物和无菌载体来制备液体单位剂型,根据使用浓度,或将化合物悬浮在载体中,或将化合物溶解在载体中。制备溶液时,将化合物溶解在注射水或注射生理盐水中,过滤消毒后装入适宜的小瓶或安瓿中,并进行封口。有益的是,添加剂如局麻药、防腐剂和缓冲剂可以溶解在载体中。适宜的缓冲剂是,例如,磷酸盐和柠檬酸盐。为了增加稳定性,可以把盛装入小瓶中的组合物经真空除去水分而冷冻干燥。非肠道悬浮液可以按照基本类似的方法制备,除外化合物是悬浮于载体中而不是溶解在载体中,而且不能用过滤来灭菌。化合物可以用常规方法灭菌,例如在悬浮于无菌载体之前,先行暴露于射线或环氧乙烷中。有益的是,组合物中包括表面活性剂或润湿剂以利于化合物的均匀分布。
现在,将以实施例的方式对本发明进行描述,这旨在说明,而不是对发明范围的限定。实施例1
实施例1中,在杏仁核点燃模型中比较2-正-丙基-4-己炔酸和丙戊酸的抗偏头痛和抗情感性疾病的特性。材料与方法动物
雌性Wister大鼠(Harlan-Winkehnann,Borchen.德国),11-12周龄(体重180-200g)。之所以使用雌性大鼠,是因为已知雌性大鼠清除药物的速度较雄性大鼠慢,这一特性被认为是药物效力研究中的优势。将大鼠分开饲养在温控(23℃)和湿控(约50%)的塑料笼中,自上午7点开始享有12小时的光照周期。大鼠接受标准饮食(Altromin;Lage,F.R.G.)、自来水和libitum。所有注射均在下午于23-25℃室温中进行。常规方案这样进行:从各个笼中取出大鼠,称重,把它们集合到工作台上6个开口的塑料笼中,以便更好地观察其行为。因而,动物能够从一个笼移动到另一个笼中,而且既可以有社会接触也可以回避接触。在大约15分钟的短暂适应之后,记录直肠体温,接着施用药物或载体。大鼠杏仁核点燃
为了将刺激和记录电极植入,用水合氯醛(360mg/kg腹腔注射)麻醉大鼠,并在basolateral杏仁核右侧将一个双极电级立体定位植入(按照Paxinos和Watson的图谱中描述的手术方法实施)。电极植入的坐标是AP-2.2mm,L-4.8mm,V-8.5mm。所有的坐标均从前囟开始测量。颅骨螺钉作为无关参考电极。用牙科丙烯酸粘固粉把装配电极固定到颅骨上。术后2周之后,以1/天的间隔向杏仁核释放恒定电流刺激(500μA,1ms,单相方波脉冲,50/s 1s),直至10次5级惊厥被点燃。使用递增阶梯样程序,在试验第一天(最初后放电阈值)以及获得点燃后(在第10次5级惊厥后以至少4天的间隔)记录刺激区域的电流敏感性(诱导后放电的阈值)。最初电流强度是10μA,以1分钟的间隔按照高于前一电流约20%的台阶增加电流强度,直至点燃持续3秒的后放电。由于几乎所有完全点燃的动物在后释放阈电流时表现为惊厥全身大发作(4-5级),因此,不必要单独测定大发作的阈值。除了后放电阈值外,还在用后放电阈值电流刺激后测定完全点燃大鼠的点燃惊厥的下列参数:惊厥强度,根据Racine(1972)划分等级:1级-不动,闭眼,触须颤搐,用力吸气(sniff),面部阵挛;2级-与更为严重的面部痉挛相关的点头;3级-一个前肢痉挛;4级-暴跳(rearing),常伴有双前肢痉挛;5级-失去平衡的暴跳和伴有全身阵挛性惊厥的摔倒。惊厥期1(SD1),是缘(limbic)(1-2级)和/或运动元惊厥(3-5级)期。惊厥期2(SD2),包括缘和/或运动元惊厥的时间加上相邻接的不动的时间。后放电期1(ADD1),是在EEG上记录的从以至少l/s的频率兴奋的点开始的尖峰信号的时间。后放电期2(ADD2),是EEG上出现尖峰信号的的总时间,包括ADD1后的低频率和低振幅。
用一组8-9只(编号784,785,787,788,789,790[由于电级脱落而不得不退出试验],791,792,793)可以重现5级惊厥的大鼠,检测了2-正-丙基-4-己炔酸和丙戊酸盐在完全点燃的大鼠模型中的抗惊厥作用。
刺激前15分钟腹腔注射药物。通常在每个药物试验前2-3天进行对照试验。关于对照试验,在用每个药物治疗之前,大鼠接受腹腔注射载体(生理盐水)。对于所有药物试验,在两个药物注射之间要间隔至少4天以避免由于药物蓄积或耐受而干扰药物效力。
用药前对照记录和注射药物后的记录之间的显著性差异,使用Wilcoxon成对秩和检验(SigmaStatat for Windows,version 1.0)来计算。副作用的定量测验
除了记录抗惊厥参数外,还观察点燃大鼠的副作用,以估测治疗指数。检测包括露天观察、旋转试验和测量体温。通常在两次不同时间,在即将施用药物或载体之前和用药13分钟后,对对照和药物试验以相同的方式进行检测。
使用直径6cm的转杆和旋转速度为8rpm,来进行旋转试验。如果动物在转杆上不能保持至少1分钟的平衡,则表明有神经缺陷。在药物试验前,必须训练大鼠,以使之在转杆上保持平衡。药物或载体处理后,对于不能在转杆上保持平衡至少1分钟的大鼠,要将大鼠重复放在转杆上两次。只有在1分钟的时间内连续3次努力均不能停留在转杆上的大鼠,才被认为表现出神经缺陷。
除了定量估测神经缺陷之外,还在笼内和把动物放在直径90-100cm的露天中,来观察2-正-丙基-4-己炔酸和丙戊酸盐给药后的行为变化。触诊腹部估测肌张力。用等级评定系统(Loscher等,1987)来测定给药后的行为缺陷程度。简言之,把动物从笼中取出,放在露天中,观察1分钟,分别评定共济失调、后肢外展、翻正反射减弱(reduced righting)、体位单调、转圈、Straub尾、竖毛、行动迟缓和运动增多(在观察期末通过触诊估测腹部的肌张力)。用0~3记录除共济失调外的所有其它参数:0-无;1-模棱两可;2-存在;3-强。对于共济失调(0-6):1-后肢轻度共济失调(后蹄蹒跚);2-明显的共济失调,伴有后腿拖拉;3-共济失调更加明显,后腿拖拉更严重;4-显著的共济失调,动物向前移动时失去平衡;5-非常显著的共济失调,动物向前移动时频繁失去平衡;6-永久性丧失翻正反射。用电子温度计测量直肠体温。每日在注射药物前称量动物体重一次。用Wilcoxon成对秩和检验计算同一组动物给药前和给药后所测得的数据之间的显著性差异,用学生成对t-检验(SigmaStat for Windows,version 1.0)计算给药前和给药后体温之间的差异。通常仅比较试验那天给药前的体温与给药后的体温之间的差异。检测药物
化合物2-丙基-4-己炔酸(MW 154)在40℃水浴中溶化约30分钟,转移到相同温度的等摩尔体积的1摩尔NaOH中。形成钠盐后,溶解在生理盐水中,按照大鼠2.5ml/kg和小鼠10ml/kg的体积分别给药。丙戊酸盐(以钠盐形式溶解在水中)是德国Desitin Arzneimittel GmbH,Hamburg惠赠的。原液浓度为100mg/ml(按游离酸计算),因而用生理盐水溶解,以接受同2-丙基-4-己炔酸相等体积的注射。本研究中使用的所有药物剂量是指游离(酸)形式。
由于两种化合物的效力不同,因此,在一个剂量试验期间在治疗和点燃刺激后立即取大鼠血浆。结果大鼠杏仁核点燃和副作用
用完全点燃的杏仁核点燃模型大鼠检测了下述剂量时两种化合物的作用:50、75、100和200mg/kg,在刺激前15分钟进行腹腔注射。丙戊酸盐的所有测试剂量均观察到显著的抗杏仁核点燃惊厥作用(表1-4)。低剂量50mg/kg和75mg/kg腹腔注射,显著增加惊厥发作电流阈值,分别平均增加109%和77%。100mg/kg腹腔注射时,观察到对所有点燃参数的显著作用。诱导后放电的平均电流阈值增加319%(表3)。如果仅用大鼠各自阈值的20%对所有大鼠进行刺激的话(数组用作点燃刺激),那么,所有大鼠均被完全保护而不发生惊厥。惊厥严重程度由5.0降至3.0。惊厥持续时间由均值81秒减至18秒,总的后放电期(ADDS)从95秒降至20秒。没有观察到行为改变和体温变化。大鼠在旋转试验中无一失败。
200mg/kg丙戊酸盐时,对点燃参数的影响是:阈值增加970%,惊厥严重程度由4.9减至1.6,惊厥持续时间由73秒降至9秒,后放电期从106秒减至9秒(表4)。正如从早先的试验所预计的那样,该剂量伴有数种副作用,如明显的共济失调(在处理后13分钟检测,均值2.8)、运动迟缓(1.0)、肌肉松弛(2.0)和寒战抖动(wet dog shakes)。但是,旋转试验中无一失败。体温升至39.2℃。表1丙戊酸盐50mg/kg抗惊厥活性和副作用
表2丙戊酸盐75mg/kg抗惊厥活性和副作用
表3丙戊酸盐100mg/kg抗惊厥活性和副作用
表4丙戊酸盐200mg/kg抗惊厥活性和副作用
动物 | 784 | 785 | 787 | 788 | 789 | 790 | 791 | 792 | 793 | X | S.E.M | 统计 | ||
点燃 | Wilcoxon | |||||||||||||
后释放阈(ADT;μA) | 对照 | 30 | 20 | 30 | 15 | 36 | 20 | 42 | 42 | 25 | 28.89 | 3.26 | ||
化合物 | 50 | 110 | 36 | 75 | 42 | 75 | 60 | 60 | 36 | 60.44 | 7.93 | 0.002 | ||
惊厥严重程度(SS;分值) | 对照 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5.00 | 0.00 | ||
化合物 | 4 | 5 | 1 | 4 | 5 | 5 | 5 | 5 | 5 | 4.33 | 0.44 | n.s. | ||
惊厥期1(SD1;sec) | 对照 | 60 | 71 | 30 | 80 | 65 | 71 | 52 | 84 | 88 | 66.78 | 5.98 | ||
化合物 | 58 | 64 | 6 | 95 | 88 | 73 | 83 | 95 | 88 | 72.22 | 9.36 | n.s. | ||
惊厥期2(SD2;sec) | 对照 | 279 | 244 | 122 | 283 | 250 | 242 | 123 | 245 | 256 | 227.11 | 20.37 | ||
化合物 | 320 | 214 | 6 | 314 | 268 | 280 | 198 | 245 | 240 | 231.67 | 31.37 | n.s. | ||
后释放期1(ADD1,sec) | 对照 | 161 | 68 | 30 | 80 | 65 | 71 | 52 | 94 | 88 | 78.78 | 12.10 | ||
化合物 | 67 | 83 | 6 | 107 | 88 | 73 | 83 | 95 | 88 | 76.67 | 9.64 | n.s. | ||
后释放期2(ADD2,sec) | 对照 | 161 | 78 | 30 | 80 | 65 | 71 | 52 | 94 | 88 | 79.89 | 12.03 | ||
化合物 | 67 | 83 | 6 | 107 | 88 | 73 | 83 | 95 | 88 | 76.67 | 9.64 | n.s. | ||
体温(℃) | t-检验 | |||||||||||||
对照日 | 给药前 | 38.8 | 39.0 | 38.5 | 39.1 | 38.8 | 38.7 | 38.9 | 39.0 | 38.9 | 38.86 | 0.06 | 对照 | |
给药后13分钟 | 38.7 | 38.6 | 38.7 | 38.80 | 38.7 | 38.8 | 39.0 | 38.7 | 38.7 | 38.71 | 0.05 | n.s. | ||
试验日 | 给药前 | 38.8 | 39.1 | 38.5 | 39.1 | 39.1 | 38.6 | 38.4 | 38.7 | 38.8 | 38.79 | 0.09 | 对照 | |
给药后13分钟 | 38.7 | 39.0 | 38.7 | 39.0 | 38.8 | 38.7 | 39.0 | 39.0 | 38.5 | 38.82 | 0.06 | n.s. |
行为 (分值) | ||||||||||||||
共济失调(1-6) | 13’ | |||||||||||||
后腿外展(1-3) | 13’ | |||||||||||||
翻正反射减弱(1-3) | 13’ | |||||||||||||
体位单调(1-3) | 13’ | |||||||||||||
旋转(1-3) | 13’ | |||||||||||||
Straub尾(1-3) | 13’ | |||||||||||||
竖毛(1-3) | 13’ | |||||||||||||
运动迟缓(1-3) | 13’ | |||||||||||||
运动过多(1-3) | 13’ | |||||||||||||
肌肉松弛(1-3) | 13’ | |||||||||||||
试验日的旋转实验 | 13’ | + | + | + | + | + | + | + | + | + | 0% | |||
动物 | 784 | 785 | 787 | 788 | 789 | 791 | 792 | 793 | X | S.E.M | 统计 | |||
点燃 | Wilcoxon | |||||||||||||
后释放阈(ADT;μA) | 对照 | 20 | 30 | 25 | 15 | 50 | 50 | 110 | 30 | 41.25 | 10.80 | |||
化合物 | 50 | 75 | 60 | 25 | 110 | 60 | 130 | 75 | 73.13 | 11.80 | 0.0039 | |||
惊厥严重程度(SS;分值) | 对照 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5.00 | 0.00 | |||
化合物 | 4 | 5 | 4 | 5 | 2 | 3 | 5 | 5 | 4.13 | 0.40 | ||||
惊厥期1(SD1;sec) | 对照 | 47 | 68 | 84 | 65 | 81 | 41 | 70 | 92 | 68.50 | 6.24 | |||
化合物 | 20 | 65 | 65 | 95 | 9 | 18 | 60 | 100 | 54.00 | 12.36 | n.s. | |||
惊厥期2(SD2;sec) | 对照 | 267 | 218 | 202 | 327 | 348 | 120 | 266 | 100 | 249.75 | 25.46 | |||
化合物 | 30 | 445 | 300 | 343 | 9 | 18 | 392 | 465 | 250.75 | 70.19 | n.s. | |||
后释放期1(ADD1,sec) | 对照 | 94 | 77 | 125 | 64 | 86 | 41 | 82 | 92 | 82.63 | 8.59 | |||
化合物 | 20 | 87 | 95 | 104 | 9 | 18 | 102 | 103 | 67.25 | 15.26 | n.s. | |||
后释放期2(ADD2,sec) | 对照 | 94 | 77 | 125 | 64 | 86 | 41 | 82 | 92 | 82.63 | 8.59 | |||
化合物 | 20 | 87 | 95 | 104 | 9 | 18 | 102 | 103 | 67.25 | 15.26 | n.s. | |||
体温(℃) | t-检验 | |||||||||||||
对照日 | 给药前 | 38.5 | 38.2 | 38.8 | 37.8 | 37.8 | 38.9 | 38.2 | 38.5 | 38.34 | 0.15 | 对照 | ||
给药后13分钟 | 38.7 | 38.8 | 38.9 | 38.9 | 38.9 | 39.1 | 38.4 | 39.0 | 38.84 | 0.08 | 0.0103 | |||
试验日 | 给药前 | 38.6 | 38.2 | 38.1 | 38.1 | 38.8 | 38.8 | 38.4 | 38.8 | 38.48 | 0.11 | 对照 | ||
给药后13分钟 | 38.7 | 39.0 | 38.6 | 38.4 | 37.4 | 39.2 | 38.4 | 38.7 | 38.55 | 0.19 | n.s. |
行为 (分值) | ||||||||||||||
共济失调(1-6) | 13’ | |||||||||||||
后腿外展(1-3) | 13’ | |||||||||||||
翻正反射减弱(1-3) | 13’ | |||||||||||||
体位单调(1-3) | 13’ | |||||||||||||
旋转(1-3) | 13’ | |||||||||||||
Straub尾(1-3) | 13’ | |||||||||||||
竖毛(1-3) | 13’ | |||||||||||||
运动迟缓(1-3) | 13’ | |||||||||||||
运动过多(1-3) | 13’ | |||||||||||||
肌肉松弛(1-3) | 13’ | |||||||||||||
试验日的旋转实验 | 13’ | + | + | + | + | + | + | + | + | 0% | ||||
动物 | 784 | 785 | 787 | 788 | 789 | 790 | 791 | 792 | 793 | X | S.E.M | 统计 | ||
点燃 | Wilcoxon | |||||||||||||
后释放阈(ADT;μA) | 对照 | 30 | 10 | 20 | 15 | 36 | 10 | 90 | 90 | 25 | 36.22 | 10.57 | ||
化合物 | 75 | 130 | 60 | 200 | 130 | 160 | 240 | 240 | 130 | 151.67 | 21.63 | 0.0020 | ||
惊厥严重程度(SS;分值) | 对照 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5.00 | 0.00 | ||
化合物 | 2 | 3 | 3 | 3 | 2 | 4 | 2 | 5 | 3 | 3.00 | 0.33 | 0.0039 | ||
惊厥期1(SD1;sec) | 对照 | 60 | 55 | 70 | 65 | 92 | 91 | 138 | 77 | 85 | 81.44 | 8.33 | ||
化合物 | 22 | 5 | 5 | 13 | 6 | 5 | 6 | 84 | 18 | 18.22 | 8.49 | 0.0039 | ||
惊厥期2(SD2;sec) | 对照 | 260 | 205 | 218 | 241 | 153 | 216 | 238 | 280 | 303 | 234.89 | 14.72 | ||
化合物 | 22 | 5 | 5 | 13 | 6 | 5 | 6 | 310 | 18 | 43.44 | 33.40 | 0.0039 | ||
后释放期1(ADD1,sec) | 对照 | 60 | 5 | 70 | 65 | 92 | 91 | 138 | 77 | 85 | 81.44 | 8.33 | ||
化合物 | 22 | 5 | 5 | 13 | 6 | 5 | 6 | 100 | 18 | 20.00 | 10.22 | 0.0039 | ||
后释放期2(ADD2,sec) | 对照 | 145 | 55 | 107 | 65 | 92 | 91 | 138 | 77 | 85 | 95.00 | 10.17 | ||
化合物 | 22 | 5 | 5 | 13 | 6 | 5 | 6 | 100 | 18 | 20.00 | 10.22 | 0.0039 | ||
体温(℃) | t-检验 | |||||||||||||
对照日 | 给药前 | 38.4 | 38.9 | 38.3 | 37.6 | 38.4 | 37.6 | 38.0 | 38.6 | 39.0 | 38.31 | 0.17 | 对照 | |
给药后13分钟 | 38.0 | 39.0 | 38.5 | 38.7 | 38.5 | 38.6 | 37.9 | 38.3 | 38.8 | 38.48 | 0.12 | n.s. | ||
试验日 | 给药前 | 38.4 | 38.5 | 38.0 | 38.5 | 38.4 | 37.8 | 38.5 | 38.2 | 38.9 | 38.36 | 0.11 | 对照 | |
给药后13分钟 | 38.9 | 38.9 | 38.9 | 39.0 | 39.0 | 39.1 | 39.2 | 38.9 | 38.8 | 38.97 | 0.04 | 0.0013 |
行为 (分值) | ||||||||||||||
共济失调(1-6) | 13’ | |||||||||||||
后腿外展(1-3) | 13’ | |||||||||||||
翻正反射减弱(1-3) | 13’ | |||||||||||||
体位单调(1-3) | 13’ | |||||||||||||
旋转(1-3) | 13’ | |||||||||||||
Straub尾(1-3) | 13’ | |||||||||||||
竖毛(1-3) | 13’ | |||||||||||||
运动迟缓(1-3) | 13’ | |||||||||||||
运动过多(1-3) | 13’ | |||||||||||||
肌肉松弛(1-3) | 13’ | |||||||||||||
试验日的旋转实验 | 13’ | + | + | + | + | + | + | + | + | 0% | ||||
动物 | 784 | 785 | 787 | 788 | 789 | 791 | 792 | 793 | X | S.E.M | 统计 | |||
点燃 | Wilcoxon | |||||||||||||
后释放阈(ADT;μA) | 对照 | 36 | 25 | 25 | 20 | 25 | 60 | 130 | 50 | 46.38 | 12.93 | |||
化合物 | 130 | 840 | 590 | 840 | 200 | 840 | 330 | 200 | 496.25 | 111.85 | 0.0039 | |||
惊觉严重程度(SS;分值) | 对照 | 5 | 5 | 5 | 5 | 5 | 4 | 5 | 5 | 4.88 | 0.13 | |||
化合物 | 2 | 3 | 3 | 1 | 1 | 1 | 1 | 1 | 1.63 | 0.32 | 0.0039 | |||
惊厥期1(SD1;sec) | 对照 | 46 | 60 | 90 | 75 | 98 | 50 | 68 | 98 | 73.13 | 7.31 | |||
化合物 | 8 | 18 | 9 | 8 | 6 | 5 | 5 | 11 | 8.75 | 1.51 | 0.0039 | |||
惊厥期2(SD2;sec) | 对照 | 321 | 229 | 338 | 241 | 361 | 232 | 298 | 295 | 289.38 | 17.87 | |||
化合物 | 8 | 18 | 9 | 8 | 6 | 5 | 5 | 11 | 8.75 | 1.51 | 0.0039 | |||
后释放期1(ADD1,sec) | 对照 | 133 | 78 | 172 | 75 | 98 | 50 | 105 | 100 | 101.38 | 13.29 | |||
化合物 | 8 | 18 | 9 | 8 | 6 | 5 | 5 | 11 | 8.75 | 1.51 | 0.0039 | |||
后释放期2(ADD2,sec) | 对照 | 133 | 78 | 172 | 111 | 98 | 50 | 105 | 100 | 105.88 | 12.77 | |||
化合物 | 8 | 18 | 9 | 8 | 6 | 5 | 5 | 11 | 8.75 | 1.51 | 0.0039 | |||
体温(℃) | t-检验 | |||||||||||||
对照日 | 给药前 | 37.9 | 38.0 | 37.7 | 38.4 | 38.3 | 38.2 | 38.1 | 37.9 | 38.06 | 0.08 | 对照 | ||
给药后13分钟 | 37.9 | 39.0 | 38.7 | 38.2 | 38.4 | 38.7 | 38.2 | 38.5 | 38.45 | 0.12 | 0.048 | |||
试验日 | 给药前 | 38.2 | 38.5 | 39.1 | 38.6 | 38.8 | 38.9 | 38.6 | 38.9 | 38.70 | 0.10 | 对照 | ||
给药后13分钟 | 39.1 | 39.7 | 39.4 | 38.6 | 39.1 | 39.3 | 38.9 | 39.3 | 39.18 | 0.12 | 0.01 |
行为 (分值) | ||||||||||||||
共济失调(1-6) | 13’ | 3 | 2 | 3 | 4 | 2 | 3 | 3 | 2 | 2.75 | 0.25 | 0.0039 | ||
后腿外展(1-3) | 13’ | |||||||||||||
翻正反射减弱(1-3) | 13’ | |||||||||||||
体位单调(1-3) | 13’ | |||||||||||||
旋转(1-3) | 13’ | |||||||||||||
Straub尾(1-3) | 13’ | |||||||||||||
竖毛(1-3) | 13’ | |||||||||||||
运动迟缓(1-3) | 13’ | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1.00 | 0.00 | 0.0039 | ||
运动过多(1-3) | 13’ | |||||||||||||
肌肉松弛(1-3) | 13’ | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 2.00 | 0.00 | 0.0039 | ||
试验日的旋转实验 | 13’ | + | + | + | + | + | + | + | + | 0% | ||||
通过比较,2-丙基-4-己炔酸在剂量50mg/kg腹腔注射时无明显作用(见表5)。75mg/kg时,阈值提高到109%,惊厥严重程度由平均得分5.0显著降至2.3(表6)。惊厥持续时间由66秒减至16秒,后放电持续时间从86秒减至16秒。100mg/kg时(表7),阈值平均提高160%。惊厥严重程度由5.0减为3.6,没有较低剂量时减少得那样多。同样,惊厥持续时间由83秒减至47秒。最大剂量取得最大抗杏仁核点燃惊厥作用。200mg/kg(表8)时,阈值平均提高209%,惊厥严重程度由4.6降至1.8。惊厥持续时间由均值62秒减至19秒,总的后放电期(ADD2)从77秒减至24秒。
仅在最高剂量200mg/kg时观察到轻微的副作用,共济失调(平均分值1.5)、运动迟缓(1.4)、肌肉松弛(1.4),并且这些副作用轻于丙戊酸盐的副作用。体温保持在生理范围,所有动物顺利通过旋转试验。表52-丙基-4-己炔酸50mg/kg抗惊厥活性和副作用
表62-丙基-4-己炔酸75mg/kg抗惊厥活性和副作用
表72-丙基-4-己炔酸100mg/kg抗惊厥活性和副作用
表82-丙基-4-己炔酸200mg/kg抗惊厥活性和副作用
动物 | 784 | 785 | 787 | 788 | 789 | 791 | 792 | 793 | X | S.E.M | 统计 | |||
点燃 | Wilcoxon | |||||||||||||
后释放阈(ADT;μA) | 对照 | 42 | 20 | 25 | 15 | 36 | 20 | 60 | 42 | 25 | 31.67 | 4.82 | ||
化合物 | 42 | 36 | 30 | 20 | 42 | 30 | 50 | 50 | 36 | 37.33 | 3.28 | n.s. | ||
惊厥严重程度(SS;分值) | 对照 | 5 | 4 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 4.89 | 0.11 | ||
化合物 | 5 | 5 | 4 | 5 | 5 | 5 | 5 | 5 | 5 | 4.89 | 0.11 | n.s. | ||
惊厥期1(SD1;sec) | 对照 | 67 | 59 | 83 | 93 | 92 | 65 | 172 | 72 | 90 | 88.11 | 11.30 | ||
化合物 | 74 | 79 | 81 | 88 | 98 | 77 | 64 | 52 | 93 | 78.44 | 4.75 | n.s. | ||
惊厥期2(SD2;sec) | 对照 | 289 | 121 | 282 | 335 | 253 | 174 | 260 | 293 | 280 | 254.11 | 22.01 | ||
化合物 | 254 | 200 | 198 | 288 | 270 | 224 | 217 | 164 | 294 | 234.33 | 14.88 | n.s. | ||
后释放期1(ADD1,sec) | 对照 | 68 | 59 | 83 | 11 | 92 | 65 | 172 | 99 | 90 | 93.22 | 11.35 | ||
化合物 | 161 | 79 | 114 | 88 | 97 | 91 | 64 | 52 | 92 | 93.11 | 10.43 | n.s. | ||
后释放期2(ADD2,sec) | 对照 | 68 | 59 | 83 | 11 | 92 | 65 | 172 | 99 | 90 | 93.22 | 11.35 | ||
化合物 | 161 | 79 | 114 | 88 | 97 | 91 | 64 | 52 | 92 | 93.11 | 10.43 | n.s. | ||
体温(℃) | t-检验 | |||||||||||||
对照日 | 给药前 | 38.0 | 38.5 | 38.1 | 37.7 | 38.6 | 38.6 | 38.4 | 38.3 | 38.8 | 38.33 | 0.12 | 对照 | |
给药后13分钟 | 38.5 | 38.4 | 38.3 | 38.4 | 38.7 | 39.0 | 38.5 | 38.2 | 38.8 | 38.53 | 0.08 | n.s. | ||
试验日 | 给药前 | 37.4 | 38.5 | 38.3 | 38.7 | 38.2 | 38.6 | 38.6 | 38.9 | 38.8 | 38.44 | 0.15 | 对照 | |
给药后13分钟 | 37.6 | 38.9 | 38.3 | 38.3 | 38.6 | 38.5 | 38.7 | 38.6 | 38.8 | 38.48 | 0.13 | n.s. |
行为 (分值) | ||||||||||||||
共济失调(1-6) | 13’ | |||||||||||||
后腿外展(1-3) | 13’ | |||||||||||||
翻正反射减弱(1-3) | 13’ | |||||||||||||
体位单调(1-3) | 13’ | |||||||||||||
旋转(1-3) | 13’ | |||||||||||||
Straub尾(1-3) | 13’ | |||||||||||||
竖毛(1-3) | 13’ | |||||||||||||
运动迟缓(1-3) | 13’ | |||||||||||||
运动过多(1-3) | 13’ | |||||||||||||
肌肉松弛(1-3) | 13’ | |||||||||||||
试验日的旋转实验 | 13’ | + | + | + | + | + | + | + | + | 0% | ||||
动物 | 784 | 785 | 787 | 788 | 789 | 791 | 792 | 793 | X | S.E.M | 统计 | |||
点燃 | Wilcoxon | |||||||||||||
后释放阈(ADT;μA) | 对照 | 36 | 10 | 36 | 10 | 30 | 90 | 90 | 36 | 42.25 | 11.11 | |||
化合物 | 18 | 90 | 90 | 90 | 110 | 90 | 160 | 60 | 88.50 | 14.25 | 0.0157 | |||
惊厥严重程度(SS;分值) | 对照 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5.00 | 0.00 | |||
化合物 | 1 | 2 | 3 | 3 | 1 | 3 | 4 | 1 | 2.25 | 0.41 | 0.0039 | |||
惊厥期1(SD1;sec) | 对照 | 48 | 64 | 80 | 65 | 92 | 42 | 54 | 85 | 66.25 | 6.38 | |||
化合物 | 18 | 6 | 7 | 5 | 8 | 35 | 26 | 25 | 16.25 | 4.03 | 0.0039 | |||
惊厥期2(SD2;sec) | 对照 | 348 | 240 | 210 | 180 | 120 | 230 | 398 | 260 | 248.25 | 31.48 | |||
化合物 | 18 | 6 | 7 | 5 | 8 | 35 | 26 | 25 | 16.25 | 4.03 | 0.0039 | |||
后释放期1(ADD1,sec) | 对照 | 108 | 79 | 107 | 65 | 106 | 42 | 93 | 85 | 85.63 | 8.24 | |||
化合物 | 18 | 6 | 7 | 5 | 8 | 35 | 26 | 25 | 16.25 | 4.03 | 0.0039 | |||
后释放期2(ADD2,sec) | 对照 | 108 | 79 | 107 | 65 | 106 | 42 | 93 | 85 | 85.63 | 8.24 | |||
化合物 | 18 | 6 | 7 | 5 | 8 | 35 | 26 | 25 | 16.25 | 4.03 | 0.0039 | |||
体温(℃) | t-检验 | |||||||||||||
对照日 | 给药前 | 38.6 | 38.9 | 39.0 | 38.7 | 38.9 | 39.2 | 39.0 | 39.2 | 38.94 | 0.08 | 对照 | ||
给药后13分钟 | 39.2 | 39.0 | 38.8 | 38.5 | 39.0 | 38.7 | 38.2 | 38.7 | 38.76 | 0.11 | n.s. | |||
试验日 | 给药前 | 37.8 | 38.2 | 38.0 | 37.9 | 38.5 | 38.3 | 37.9 | 38.4 | 38.13 | 0.09 | 对照 | ||
给药后13分钟 | 38.3 | 38.6 | 38.8 | 38.6 | 38.5 | 38.6 | 38.2 | 38.3 | 38.49 | 0.07 | 0.0133 |
行为 (分值) | ||||||||||||||
共济失调(1-6) | 13’ | |||||||||||||
后腿外展(1-3) | 13’ | |||||||||||||
翻正反射减弱(1-3) | 13’ | |||||||||||||
体位单调(1-3) | 13’ | |||||||||||||
旋转(1-3) | 13’ | |||||||||||||
Straub尾(1-3) | 13’ | |||||||||||||
竖毛(1-3) | 13’ | |||||||||||||
运动迟缓(1-3) | 13’ | |||||||||||||
运动过多(1-3) | 13’ | |||||||||||||
肌肉松弛(1-3) | 13’ | |||||||||||||
试验日的旋转实验 | 13’ | + | + | + | + | + | + | + | + | 0% | ||||
动物 | 784 | 785 | 787 | 788 | 789 | 791 | 792 | 793 | X | S.E.M | 统计 | |||
点燃 | Wilcoxon | |||||||||||||
后释放阈(ADT;μA) | 对照 | 42 | 36 | 20 | 25 | 30 | 75 | 130 | 30 | 48.50 | 13.09 | |||
化合物 | 60 | 130 | 75 | 200 | 110 | 200 | 160 | 75 | 126.25 | 19.79 | 0.0039 | |||
惊厥严重程度(SS;分值) | 对照 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5.00 | 0.00 | |||
化合物 | 5 | 4 | 2 | 3 | 2 | 3 | 5 | 5 | 3.63 | 0.46 | 0.0313 | |||
惊厥期1(SD1;sec) | 对照 | 60 | 90 | 80 | 79 | 114 | 67 | 84 | 90 | 83.00 | 5.78 | |||
化合物 | 57 | 5 | 5 | 5 | 10 | 130 | 75 | 85 | 46.50 | 16.84 | 0.0274 | |||
惊厥期2(SD2;sec) | 对照 | 310 | 280 | 200 | 318 | 261 | 168 | 280 | 253 | 258.75 | 18.31 | |||
化合物 | 180 | 5 | 5 | 5 | 10 | 130 | 275 | 235 | 105.63 | 40.33 | 0.0039 | |||
后释放期1(ADD1,sec) | 对照 | 71 | 90 | 80 | 93 | 114 | 67 | 84 | 89 | 86.00 | 5.15 | |||
化合物 | 145 | 5 | 5 | 5 | 10 | 130 | 107 | 95 | 62.75 | 21.99 | n.s. | |||
后释放期2(ADD2,sec) | 对照 | 78 | 90 | 80 | 93 | 14 | 67 | 84 | 89 | 86.88 | 4.85 | |||
化合物 | 145 | 5 | 5 | 5 | 10 | 130 | 107 | 95 | 62.75 | 21.99 | n.s. | |||
体温(℃) | t-检验 | |||||||||||||
对照日 | 给药前 | 38.5 | 38.4 | 38.2 | 38.6 | 39.0 | 38.5 | 38.2 | 38.2 | 38.45 | 0.10 | 对照 | ||
给药后13分钟 | 38.4 | 38.6 | 38.1 | 38.8 | 38.8 | 38.6 | 38.4 | 38.5 | 38.52 | 0.0 | n.s. | |||
试验日 | 给药前 | 38.4 | 38.7 | 38.7 | 38.9 | 39.1 | 38.4 | 38.6 | 38.9 | 38.71 | 0.09 | 对照 | ||
给药后13分钟 | 38.3 | 38.7 | 38.4 | 38.1 | 38.1 | 38.5 | 38.0 | 38.4 | 38.31 | 0.08 | 0.0236 |
行为 (分值) | ||||||||||||||
共济失调(1-6) | 13’ | |||||||||||||
后腿外展(1-3) | 13’ | |||||||||||||
翻正反射减弱(1-3) | 13’ | |||||||||||||
体位单调(1-3) | 13’ | |||||||||||||
旋转(1-3) | 13’ | |||||||||||||
Straub尾(1-3) | 13’ | |||||||||||||
竖毛(1-3) | 13’ | |||||||||||||
运动迟缓(1-3) | 13’ | |||||||||||||
运动过多(1-3) | 13’ | |||||||||||||
肌肉松弛(1-3) | 13’ | |||||||||||||
试验日的旋转实验 | 13’ | + | + | + | + | + | + | + | + | 0% | ||||
动物 | 784 | 785 | 787 | 788 | 789 | 791 | 792 | 793 | X | S.E.M | 统计 | |||
点燃 | Wilcoxon | |||||||||||||
后释放阈(ADT;μA) | 对照 | 42 | 20 | 30 | 15 | 30 | 200 | 90 | 36 | 57.88 | 21.87 | |||
化合物 | 110 | 160 | 160 | 200 | 110 | 330 | 160 | 200 | 178.75 | 24.74 | 0.0039 | |||
惊厥严重程度(SS;分值) | 对照 | 5 | 5 | 5 | 5 | 4 | 3 | 5 | 5 | 4.63 | 0.26 | |||
化合物 | 1 | 1 | 5 | 1 | 1 | 1 | 3 | 1 | 1.75 | 0.53 | 0.0078 | |||
惊厥期1(SD1;sec) | 对照 | 50 | 65 | 87 | 82 | 47 | 10 | 62 | 90 | 61.63 | 9.34 | |||
化合物 | 10 | 4 | 78 | 5 | 8 | 8 | 25 | 16 | 19.25 | 8.73 | 0.0039 | |||
惊厥期2(SD2;sec) | 对照 | 298 | 240 | 224 | 210 | 120 | 10 | 290 | 191 | 197.88 | 33.41 | |||
化合物 | 10 | 4 | 215 | 5 | 8 | 25 | 16 | 36.38 | 25.63 | 0.0039 | ||||
后释放期1(ADD1,sec) | 对照 | 107 | 77 | 107 | 82 | 47 | 10 | 99 | 89 | 77.25 | 11.83 | |||
化合物 | 10 | 4 | 112 | 5 | 8 | 25 | 16 | 23.50 | 12.87 | 0.0117 | ||||
后释放期2(ADD2,sec) | 对照 | 194 | 77 | 107 | 82 | 47 | 10 | 99 | 89 | 88.13 | 18.73 | |||
化合物 | 10 | 4 | 112 | 5 | 8 | 8 | 25 | 16 | 23.50 | 12.87 | 0.0117 | |||
体温(℃) | t-检验 | |||||||||||||
对照日 | 给药前 | 38.4 | 38.6 | 38.9 | 39.1 | 38.7 | 39.3 | 38.9 | 38.8 | 38.84 | 0.10 | 对照 | ||
给药后13分钟 | 38.8 | 38.7 | 38.3 | 38.2 | 37.9 | 38.5 | 38.1 | 38.4 | 38.36 | 0.11 | 0.0266 | |||
试验日 | 给药前 | 38.7 | 38.7 | 38.4 | 38.5 | 38.4 | 39.1 | 38.2 | 39.4 | 38.68 | 0.14 | 对照 | ||
给药后13分钟 | 37.4 | 38.5 | 38.0 | 38.0 | 37.4 | 38.4 | 38.0 | 37.8 | 37.94 | 0.14 | 0.0050 |
行为 (分值) | ||||||||||||||
共济失调(1-6) | 13’ | 2 | 1 | 1 | 3 | 2 | 2 | 2 | 1 | 1.50 | 0.33 | 0.0078 | ||
后腿外展(1-3) | 13’ | |||||||||||||
翻正反射减弱(1-3) | 13’ | 2 | 1 | 1 | 1 | 1 | 0.75 | 0.25 | 0.0313 | |||||
体位单调(1-3) | 13’ | |||||||||||||
旋转(1-3) | 13’ | |||||||||||||
Straub尾(1-3) | 13’ | |||||||||||||
竖毛(1-3) | 13’ | |||||||||||||
运动迟缓(1-3) | 13’ | 2 | 2 | 1 | 2 | 1 | 1 | 2 | 1.38 | 0.26 | 0.0078 | |||
运动过多(1-3) | 13’ | |||||||||||||
肌肉松弛(1-3) | 13’ | 2 | 2 | 1 | 1 | 2 | 1 | 2 | 1.38 | 0.26 | 0.0078 | |||
试验日的旋转实验 | 13’ | + | + | + | + | + | + | + | + | 0% | ||||
如表9所示,施用同样剂量的丙戊酸和2-丙基-4-己炔酸后,血浆药物浓度相当。另外,药物溶解度实验表明:丙戊酸和2-丙基-4-己炔酸分别是20mg/ml和18.5mg/ml。因此,溶液中两种化合物的药物浓度无显著性差异,提示两化合物之间药物效力的差异并非是由于溶解度的差异所致的。
丙戊酸 | 2-正-丙基-4-己炔酸 | |
784 | 173.37 | 154.89 |
785 | 205.44 | 220.70 |
787 | 174.06 | 180.10 |
788 | 157.83 | 170.68 |
789 | 190.82 | 225.95 |
791 | 197.82 | 209.31 |
792 | 189.87 | 201.34 |
793 | 168.89 | 218.87 |
均值 | 182.26 | 198.37 |
Claims (14)
1.治疗和/或预防哺乳动物偏头痛与情感性疾病的方法,包括向所述哺乳动物施用治疗有效量的2-正-丙基-4-己炔酸或其药物可接受的盐,其中2-正-丙基-4-己炔酸的形式选自消旋、单对映体或对映体的非-消旋混合物。
2.按照权利要求1所述的方法,其中化合物是(R)-2-丙基-4-己炔酸。
3.按照权利要求1所述的方法,其中化合物是(S)-2-丙基-4-己炔酸。
4.按照权利要求1所述的方法,其中化合物是2-丙基-4-己炔酸的可药用盐。
5.按照权利要求2所述的方法,其中化合物是(R)-2-丙基-4-己炔酸的可药用盐。
6.按照权利要求3所述的方法,其中化合物是(S)-2-丙基-4-己炔酸的可药用盐。
7.按照权利要求1所述的方法,其中2-正-丙基-4-己炔酸按照选自下述途径中的至少一种来施用:非胃肠道、口服、静脉内、肌内、皮下和直肠给药。
8.按照权利要求1所述的方法,其中情感性疾病是双相性疾病。
9.按照权利要求1所述的方法,其中被治疗的情感性疾病是躁狂症急性期。
10.按照权利要求1所述的方法,其中2-正-丙基-4-己炔酸用于预防偏头痛。
11.按照权利要求1所述的方法,其中2-正-丙基-4-己炔酸给药量为约1-60mg/kg/天。
12.按照权利要求11所述的方法,其中剂量大约是10-20mg/kg/天。
13.按照权利要求11所述的方法,其中2-正-丙基-4-己炔酸用于治疗躁狂症。
14.按照权利要求11所述的方法,其中2-正-丙基-4-己炔酸用于治疗和/或预防偏头痛。
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USRE46060E1 (en) | 1997-02-10 | 2016-07-05 | Genesys Telecommunications Laboratories, Inc. | In-band signaling for routing |
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CA2372806A1 (en) * | 1999-05-04 | 2000-11-09 | Keith R. Edwards | Intravenous valproate for acute treatment of migraine headache |
KR100843703B1 (ko) | 2000-07-21 | 2008-07-04 | 이섬 리서치 디벨러프먼트 컴파니 오브 더 히브루 유니버시티 오브 예루살렘 | 양극성 장애에서의 조증을 치료하기 위한 벨프로익산 및 2-벨프로에닉산 아미드 유도체의 용도 |
MXPA03001458A (es) * | 2000-08-17 | 2004-05-04 | Teva Pharma | Derivados de acido valproico para el tratamiento del dolor. |
US20020103110A1 (en) * | 2001-01-26 | 2002-08-01 | Spitzer A. Robert | System and method for rectal administration of medication for treatment of migraines |
US7968569B2 (en) * | 2002-05-17 | 2011-06-28 | Celgene Corporation | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
WO2004037843A2 (en) * | 2002-10-25 | 2004-05-06 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Steroid compounds comprising superoxide dismutase mimic groups and nitric oxide donor groups, and their use in the preparation of medicaments |
WO2004050084A2 (en) * | 2002-11-29 | 2004-06-17 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Ace-inhibitors having antioxidant and nitricoxid-donor activity |
CA2508855A1 (en) * | 2002-12-16 | 2004-07-01 | Frank Slade Abbott | Valproic acid analogues and pharmaceutical compositions thereof |
EP1543831A1 (en) * | 2003-12-18 | 2005-06-22 | Pfizer GmbH Arzneimittelwerk Gödecke | Pregabalin composition |
WO2006012603A2 (en) * | 2004-07-22 | 2006-02-02 | Nps Pharmaceuticals, Inc. | Analogs of isovaleramide, a pharmaceutical composition including the same, and a method of treating central nervous system conditions or diseases |
US20080234213A1 (en) * | 2005-09-02 | 2008-09-25 | Matthias Wabl | Oncogenic regulatory RNAs for diagnostics and therapeutics |
US7459280B2 (en) * | 2006-02-27 | 2008-12-02 | Picobella, Llc | Methods for diagnosing and treating kidney cancer |
US20080267977A1 (en) * | 2007-04-26 | 2008-10-30 | Friedrich-Alexander University Of Erlangen-Nuremberg | Combined immunological agent and sensitizing agent for the treatment of cancer |
AU2013257710B2 (en) * | 2012-05-08 | 2016-10-20 | Cellixbio Private Limited | Compositions and methods for the treatment of neurological disorders |
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IT1283489B1 (it) | 1996-07-23 | 1998-04-21 | Chiesi Farma Spa | Ammidi di alfa-amminoacidi,loro preparazione e loro impiego terapeutico |
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1999
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- 1999-06-22 EP EP99930555A patent/EP1089725A1/en not_active Withdrawn
- 1999-06-22 KR KR1020007014630A patent/KR20010071572A/ko not_active Application Discontinuation
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- 1999-06-22 PL PL99345364A patent/PL345364A1/xx not_active Application Discontinuation
- 1999-06-22 US US09/337,986 patent/US6268396B1/en not_active Expired - Fee Related
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE46060E1 (en) | 1997-02-10 | 2016-07-05 | Genesys Telecommunications Laboratories, Inc. | In-band signaling for routing |
Also Published As
Publication number | Publication date |
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KR20010071572A (ko) | 2001-07-28 |
CZ20004833A3 (cs) | 2002-01-16 |
EP1089725A1 (en) | 2001-04-11 |
NO20006506L (no) | 2001-02-21 |
PL345364A1 (en) | 2001-12-17 |
NO20006506D0 (no) | 2000-12-20 |
AU752192B2 (en) | 2002-09-12 |
AU4707199A (en) | 2000-01-10 |
MXPA00012808A (es) | 2002-04-24 |
HUP0102456A2 (hu) | 2001-10-28 |
CA2335641A1 (en) | 1999-12-29 |
BR9911421A (pt) | 2001-03-27 |
SK19992000A3 (sk) | 2001-08-06 |
IL140415A0 (en) | 2002-02-10 |
US6268396B1 (en) | 2001-07-31 |
ZA200007652B (en) | 2002-03-19 |
TR200103249T2 (tr) | 2002-05-21 |
TR200003800T2 (tr) | 2001-06-21 |
HUP0102456A3 (en) | 2003-07-28 |
BG105163A (en) | 2002-03-29 |
WO1999066920A1 (en) | 1999-12-29 |
JP2002518442A (ja) | 2002-06-25 |
BG63744B1 (bg) | 2002-11-29 |
AU5207199A (en) | 2000-01-24 |
US6458840B2 (en) | 2002-10-01 |
US20010031789A1 (en) | 2001-10-18 |
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